Varicose veins have a thickening wall. Their smooth muscle cells are disorganized as regards proliferation and production of extracellular matrix protein. An imbalance between the synthesis of collagen type I protein (collagen I) and collagen type III protein (collagen III) could explain the lack of elasticity of varicose veins. Therefore, collagen synthesis was compared in the media and in cultured smooth muscle cells derived from human control and varicose saphenous veins. An increase in total collagen synthesis was observed in the media and in smooth muscle cells derived from varicose veins. This augmentation was due to an overproduction of collagen I in cultured cells from varicose veins consistent with an increase in the release of collagen I metabolites in the media. A concomitant decrease in collagen III was observed in cultures of smooth muscle cells from varicose veins. The increase in the synthesis of collagen I in cells from varicose veins was correlated with an overexpression of the gene since mRNAs for collagen I were augmented without change in mRNA-half-life. This augmentation in the synthesis of collagen I was reduced by the addition of exogenous collagen III in cultures from varicose veins. These findings suggest a dysregulation of the synthesis of collagen I and III in smooth muscle cells derived from varicose veins.

Erectile dysfunction (ED) is another manifestation of vascular disease. We evaluated the natural history of ED in the spontaneously hypertensive rat (SHR) and the respective participation of associated pathophysiological modifications, i.e., endothelial dysfunction and tissue remodeling. SHR and their normotensive counterparts [Wistar-Kyoto rats (WKY)] of 6, 12, and 24 wk of age (n = 12) were used to evaluate erectile function, erectile and aortic tissue reactivity, and remodeling. Erectile responses in SHR are reduced at all ages (P < 0.001). In both aortic and erectile tissues of SHR and WKY, relaxations to ACh are altered progressively with age, although more markedly in SHR. They are decreased at 12 wk of age in erectile tissue of SHR compared with WKY (maximal relaxation: -19.2 +/- 2.8% vs. -28.3 +/- 3.9%, P < 0.001) but only at 24 wk of age in aortas (-47.9 +/- 6.4% vs. -90.5 +/- 2.9%, P < 0.001). Relaxations to sodium nitroprusside are unaltered in aortic rings of both strains but enhanced in erectile tissue of SHR at 12 wk of age. Major modifications in the distribution of collagen I, III, and V in SHR occur in both types of tissue and are detectable sooner in erectile tissue compared with aortic tissue. The onset of ED is detectable before the onset of hypertension in the SHR. Structural and functional alterations, while similar, occur earlier in erectile compared with vascular tissue. If confirmed in humans, ED could be an early warning sign for hypertension, and common therapeutic strategies targeting both ED and hypertension could be investigated.

Burn-related skin fibrosis leads to loss of tissue function and hypertrophic scar formation with damaging consequences for the patient. There is therefore a great need for an efficient agent to treat burned skin. We report that ReGeneraTing Agent (RGTA) reduces burn-induced skin alteration. The tissue-regenerating effect of RGTA OTR4120 was evaluated after 1-6 days and after 10 months in a rat skin burn model. This effect was also examined in vitro using fibroblasts isolated from control and 6-day-old burned skins. We measured production of dermal collagen I, III, and V and activities of metalloproteinases 2 and 9 (MMP-2 and MMP-9). Ratio of collagen III over collagen I production increased 6 days after the burn, because of a decrease in collagen I production. After 10 months, ratio of collagen III over collagen I in burn sites was still increased compared with control skin, because of an increase in collagen III production. Both abnormalities were corrected by OTR4120. OTR4120 increased pro-and active MMP-2 and MMP-9, compared with healthy and burned controls and therefore accelerated remodeling. Similar data were obtained with cultured fibroblasts from healthy and burned skins. OTR4120 enhanced healing in short-and long-term after burns, reducing the formation of fibrotic tissue, and then represents a potential agent to improve burned skin healing.